Features of proteins that confer metabolic instability are called degradation signals, or degrons (Varshavsky, Cell 64: 13-15 (1991)). The essential component of one degradation signal, termed the N-degron, is a destabilizing N-terminal residue of a protein (Bachmair, et al., Science 234: 179-186 (1986)). A set of N-degrons containing different destabilizing residues is referred to as the N-end rule, which relates the in vivo half-life of a protein to the identity of its N-terminal residue (for review see Varshavsky, Cell 69: 725-735 (1992) and Varshavsky, Cold Spring Harbor Symp. Quant. Biol. 60: 461-478 (1996)). The N-end rule pathway has been found in all species examined, including the eubacterium Escherichia coli, the yeast Saccharomyces cerevisiae, and mammalian cells. The N-end rules of these organisms are similar but distinct.
As discussed in greater detail below, ongoing studies have revealed that the N-end rule pathway participates in a variety of complex functions in eukaryotic systems. Such studies indicate that the ability to intervene at the molecular level to inhibit or modulate the N-end rule pathway offers an important therapeutic avenue. Given the relatively complex enzymology of the pathway, the availability of components in quantity is essential to the development of therapeutic methods.